Synthesis of phospholipid headgroups via nucleophilic ring opening of 1,3,2-dioxaphospholanes

Kim, Ui T.; Hajdu, Joseph

doi:10.1039/c39930000070

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…1,2‐SiPC ( 1 ) was synthesized by adding 2‐chloro‐1,3,2‐dioxaphospholane‐2‐oxide to a solution of 6 in toluene to afford intermediate 7 . The insoluble NEt 3 · HCl salts were removed by filtration and the remaining solvent was evaporated to give a slightly opaque viscous oil that was phosphate positive showing a single 31 P NMR resonance at 17.3 ppm; as per previous reports, this compound was not characterized further but was used in the reaction as soon as possible to avoid hydrolysis of the dioxaphospholane ring.…”

Section: Resultsmentioning

confidence: 99%

A short synthesis of siloxane phosphocholines

Frampton

Zelisko

2016

Euro J Lipid Sci & Tech

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Herein, we report our first generation synthesis of two new silicon‐containing phosphocholines (SiPCs) in which the fatty acid chains are terminated by trisiloxane units. We have been exploring the limits to which immobilized lipases can be used in the field of organosilicon chemistry, and the cornerstone of this work is a chemoenzymatic approach to synthesizing SiPCs that are structurally analogous to naturally occurring species such as 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC). Practical applications: This research focuses on the chemoenzymatic synthesis of siloxane‐containing phospholipid systems. These compounds have different surface properties than the comparable biologically relevant phospholipids opening the doors for the potential application of these siloxane‐containing species as encapsulation/delivery vehicles and as a means of modifying surfaces. Surface pressure‐molecular area isotherms for siloxane‐phospholipids.

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Section: Resultsmentioning

confidence: 99%

A short synthesis of siloxane phosphocholines

Frampton

Zelisko

2016

Euro J Lipid Sci & Tech

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“…To achieve efficient phosphorylation of the substituted glyceric acid derivatives we used 2-chloro-2-oxo-1,3,2-dioxaphospholane, as this reagent has been shown to produce phosphocholine derivatives in good yields and with few byproducts, even in reactions with substrates that carry nucleophilic amide-carbonyl groups that are widely regarded as rather difficult substrates to phosphorylate. 19 Thus, reaction between ethylene chlorophosphate and the substituted glyceric acid series of 13 and/or 17 in benzene, in the presence of triethylamine as catalyst, followed by nucleophilic ring-opening of the cyclic phosphodiester intermediates with trimethylamine in anhydrous acetonitrile produced the corresponding phosphocholine compounds (Scheme 2). …”

Section: Resultsmentioning

confidence: 99%

Synthesis of phospholipids on a glyceric acid scaffold: design and preparation of phospholipase A2 specific substrates

Rosseto

Hajdu

2014

Tetrahedron

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Synthesis of a new series of phospholipid analogues to serve as activity-based probes of secretory phospholipase A2 enzymes is reported. The synthesis is based upon 1) preparation of long-chain esters and amides of glyceric acid, followed by 2) regioselective derivatization of the diol function of the molecule to achieve phosphorylation at the primary hydroxyl group, and to introduce the incipient sn-2-ester group of the target compounds. The sequence has been shown to allow incorporation of fluorescent, paramagnetic, and redox-active reporter groups, leading to phospholipid analogues applicable to detect and measure enzyme activity, to develop highly specific, real-time spectroscopic assay of phospholipase A2 enzymes, as well as to track the metabolic fate of the hydrolysis products. The synthetic method has a great deal of flexibility to open the way to the design and synthesis of activity-probes for other phospholipid metabolizing enzymes as well.

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“…For elaboration of the sn -3-phosphocholine headgroup we have modified the traditional procedure (Kim and Hajdu, 1993; Roodsari et al, 1999) by using anhydrous trimethylamine both as a catalyst in phosphorylation and as a nucleophile in the subsequent ring-opening step. Significantly, the two-step one-pot procedure eliminates the need to isolate the reactive dioxaphospholane intermediate.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of mixed-chain phosphatidylcholines including coumarin fluorophores for FRET-based kinetic studies of phospholipase A2 enzymes

Wang

Pinnamaraju

Ranganathan

et al. 2013

Chemistry and Physics of Lipids

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Phospholipase A2 (PLA2) enzymes catalyze the hydrolysis of the sn-2 ester linkage of glycerophospholipids to produce fatty acids and lysophospholipids. A significant number of mammalian phospholipases comprise a family of secreted PLA2 enzymes, found in specific tissues and cellular locations, exhibiting unique enzymatic properties and distinct biological functions. Development of new real-time spectrofluorimetric PLA2 assays should facilitate the kinetic characterization and mechanistic elucidation of the isozymes in vitro, with the potential applicability to detect and measure catalytic PLA2 activity in tissues and cellular locations. Here we report a new synthesis of double-labeled phosphatidylcholine analogues with chain-terminal reporter groups including coumarin fluorophores for fluorescence resonance energy transfer (FRET)-based kinetic studies of PLA2 enzymes. The use of coumarin derivatives as fluorescent labels provides reporter groups with substantially decreased size compared to the first generation of donor-acceptor pairs of fluorescent phospholipids. The key advantage of the design is to interfere less with the physicochemical properties of the acyl chains, thereby improving the substrate quality of the synthetic probes. In order to assess the impact of the fluorophore substituents on the catalytic hydrolysis and on the phospholipid packing in the lipid-water interface of the assay, we used the experimentally determined specific activity of bee-venom phospholipase A2 as a model for the secretory PLA2 enzymes. Specifically, the rate of PLA2 hydrolysis of the coumarin labeled phosphatidylcholine analogues was less than three times slower than natural substrate dipalmitoyl phosphatidylcholine (DPPC) under the same experimental conditions. Furthermore, variation of the mole fraction of the synthetic phosphatidylcholine vs. that of the natural DPPC substrate showed nearly ideal mixing behavior in the phospholipid-surfactant aggregates of the assay. The synthesis provides a rapid and efficient method for preparation of new synthetic phosphatidylcholines with the desired target structures for enzymatic and physicochemical studies.

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Synthesis of phospholipid headgroups via nucleophilic ring opening of 1,3,2-dioxaphospholanes

Cited by 10 publications

References 11 publications

A short synthesis of siloxane phosphocholines

A short synthesis of siloxane phosphocholines

Synthesis of phospholipids on a glyceric acid scaffold: design and preparation of phospholipase A2 specific substrates

Synthesis of mixed-chain phosphatidylcholines including coumarin fluorophores for FRET-based kinetic studies of phospholipase A2 enzymes

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